The long term objective of this proposed research is to elucidate the mechanisms that underlie the unmasking and subsequent pharmacologic activation of latent respiratory motor pathways to restore function to respiratory muscles paralyzed by spinal cord injury. The present application proposes multiple pharmacologic manipulations of the respiratory system to demonstrate that the respiratory output can be enhanced further to improve respiratory function after spinal cord injury (SCI). We will address clinically-relevant issues attendant to the use of theophylline in spinal cord injured patients. First, we will focus in on selective peripherally-mediated mechanisms that can minimize respiratory muscle fatigue that may be attendant to prolonged methylxanthine (theophylline) use. We will also focus in on putative mechanisms that may underlie the clinical observation that some spinal cord injured patients are nonresponsive to theophylline therapy. There are three specific aims to test the following hypotheses: (1) that following pharmacological activation of peripheral chemoreceptors in the carotid bodies, theophylline-induced respiratory muscle recovery can be modulated to more closely approximate normal firing frequencies. (2) that the GABA B receptor agonist, baclofen, used frequently in SCI patients as an antispasticity and muscle relaxant medication, does not modify theophylline's ability to restore function to paralyzed respiratory muscle following upper cervical spinal cord hemisection. (3) that the systemic administration of 4-aminopyridine (4AP), a potassium channel blocker, will enhance conduction in partially demyelinated latent respiratory axons and thus improve theophylline's action of restoring function to paralyzed respiratory muscle after cervical spinal cord injury.